Sleep typically occupies about one-third of a person's life and affects a person's mental and physical well-being. It additionally affects mood, behavior and physiology. Sleep and the control of sleep is a complex process involving multiple chemicals and brain structures. It is a dynamic process involving distinct physiological changes and involves both positive and negative signaling. The regulation of sleep in humans is governed by three processes—each influenced by hormonal and environmental factors: a daily sleep-wake cycle influenced by a circadian rhythm (24 hour cycle) tied to light-dark cycles controlled by a cluster of about 10,000 neurons located in the hypothalamus behind the eyes, called the suprachiasmatic nuclei (Hastings M H. Central clocking. Trends Neurosci. October 1997; 20(10):459-64); a separable oscillating sleep homeostatic process influenced by prior sleep (Dijk D J, Lockley S W. Integration of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol. February 2002; 92(2):852-62); and an ultradian rhythm which occurs within the 24 hour circadian cycle.
The need for sleep is a biological drive similar to thirst or hunger. Interestingly though, the function of sleep is largely unknown, however some evidence indicates that sleep is required for learning (Stickgold R, James L, Hobson J A. Visual discrimination learning requires sleep after training. Nat Neurosci. December 2000; 3(12):1237-8; Gais S, Plihal W, Wagner U, Born J. Early sleep triggers memory for early visual discrimination skills. Nat Neurosci. December 2000; 3(12):1335-9). Additionally, sleep deprivation studies in rats have shown that when rats are not allowed to sleep, the end-result is death apparently related to immune system failure (Everson C A. Sustained sleep deprivation impairs host defense. Am J Physiol. November 1993; 265(5 Pt 2):R1148-54). In humans, similarly, mild sleep deprivation also results in indications of impaired immune system function (Irwin M, McClintick J, Costlow C, Fortner M, White J, Gillin J C. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J. April 1996; 10(5):643-53). Although specific sleep requirements vary from individual to individual, sleeping less than six hours per day has been shown to increase the risk of glucose intolerance and diabetes (Gottlieb D J, Punjabi N M, Newman A B, Resnick H E, Redline S, Baldwin C M, Nieto F J. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. Apr. 25, 2005; 165(8):863-7). Insomnia has been estimated to affect 40% of North Americans per year (Stoller M K. Economic effects of insomnia. Clin Ther. September-October 1994; 16(5):873-97). A study by the U.S. National Sleep Foundation and the Gallup Organization involving 1,000 randomly selected Americans revealed that insomnia negatively impacts activities during waking function and effects quality of life (Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II. Sleep. May 1, 1999; 22 Suppl 2:S354-8). Another study involving 261 insomnia sufferers and 101 individuals with no sleep complaints revealed that insomnia significantly impairs quality of life (Zammit G K, Weiner J, Damato N, Sillup G P, McMillan C A. Quality of life in people with insomnia. Sleep. May 1, 1999; 22 Suppl 2:S379-85).
The neurotransmitter Gamma Aminobutyric Acid (GABA) is a primary inhibitory neurotransmitter. One of its effects is to induce sleep. The GABA-receptors are associated with chloride ion channels—signaling through the GABA-receptor changes the electrochemical gradient of the neuron, leading to activity inhibition (Olsen R W, Tobin A J. Molecular biology of GABAA receptors. FASEB J. March 1990; 4(5):1469-80). Benzodiazepines are thought to act via interaction with the GABA receptor; enhancing the inhibitory effects of GABA. As such, Benzodiazepines are a widely used class of drugs primarily used as tranquilizers, muscle-relaxants, hypnotics or sedatives (Valenstein M, Taylor K K, Austin K, Kales H C, McCarthy J F, Blow F C. Benzodiazepine use among depressed patients treated in mental health settings. Am J Psychiatry. April 2004; 161(4):654-61). Additionally, Adenosine, a neuromodulator, may induce sleep by extracellular accumulation in specific brain regions such as the basal forebrain during prolonged wakefulness (Strecker R E, Morairty S, Thakkar M M, Porkka-Heiskanen T, Basheer R, Dauphin L J, Rainnie D G, Portas C M, Greene R W, McCarley R W. Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res. November 2000; 115(2):183-204; Zeitzer J M, Morales-Villagran A, Maidment N T, Behnke E J, Ackerson L C, Lopez-Rodriguez F, Fried I, Engel J Jr, Wilson C L. Extracellular adenosine in the human brain during sleep and sleep deprivation: an in vivo microdialysis study. Sleep. Apr. 1, 2006; 29(4):455-61). Actions on both the GABA-benzodiazepine receptor complex (Mendelson W B. Sleep-inducing effects of adenosine microinjections into the medial preoptic area are blocked by flumazenil. Brain Res. Jan. 10, 2000; 852(2):479-81) and/or the adenosine A1 receptor (Thakkar M M, Winston S, McCarley R W. A1 receptor and adenosinergic homeostatic regulation of sleep-wakefulness: effects of antisense to the A1 receptor in the cholinergic basal forebrain. J Neurosci. May 15, 2003; 23(10):4278-87) can lead to the induction and maintenance of sleep. The stimulatory effects of caffeine are thought to be due to antagonism of adenosine A1 receptors (Sawynok J. Pharmacological rationale for the clinical use of caffeine. Drugs. January 1995; 49(1):37-50), wherein an aroused state is observed.
Another chemical associated with sleep is Melatonin. It is a hormone produced by the pineal gland from the amino acid tryptophan. Production is rhythmic in keeping with an intrinsic cycle of approximately 24-hours in duration, wherein levels are low during the day and increasing towards the nighttime (Wyatt J K, Ritz-De Cecco A, Czeisler C A, Dijk D J. Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. Am J Physiol. October 1999; 277(4 Pt 2):R1152-63). Melatonin appears to have two distinct effects on the circadian clock: neuronal inhibition and phase-shifting of the sleep cycle (Liu C, Weaver D R, Jin X, Shearman L P, Pieschl R L, Gribkoff V K, Reppert S M. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. July 1997; 19(1):91-102). Oral administration of supplemental melatonin during the day induces sleepiness and improves night sleep (Dollins A B, Zhdanova I V, Wurtman R J, Lynch H J, Deng M H. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA. Mar. 1, 1994; 91(5):1824-8). Two types of melatonin G-protein coupled receptors have been classified in mammals and termed MT1 and MT2 (Dubocovich M L, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. July 2005; 27(2):101-10).
Serotonin (5-hydroxytryptamine, 5HT), like melatonin, also displays a diurnal pattern; however, it functions in an opposing rhythm with daytime levels being higher than nighttime levels Portas C M, Bjorvatn B, Fagerland S, Gronli J, Mundal V, Sorensen E, Ursin R. On-line detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat. Neuroscience. April 1998; 83(3):807-1). Three basic serotonin receptor types have been identified: 5HT-1, 5HT-2 and 5HT-3. Several subtypes of 5HT-1 have also been identified. The exact response of cells to serotonin depends on the receptor types expressed (Andrade R. of membrane excitability in the central nervous system by serotonin receptor subtypes. Ann N Y Acad Sci. Dec. 15, 1998; 861:190-203) however, Serotonin has been shown to inhibit GABA receptors (Feng J, Cai X, Zhao J, Yan Z. Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci. Sep. 1, 2001; 21(17):6502-11), likely contributing to the opposing actions of serotonin and GABA and play a role in sleep.